The development of techniques for molecular imaging of disease will likely lead to improvements in patient care through early diagnosis and customized phenotype-based treatment. Much of the recent progress in molecular imaging has been technology refinement whereby novel targeted probes and imaging algorithms have been tested in various models of disease. For cardiovascular applications, there is has been particular interest on imaging immune responses that play a critical role in atherosclerosis, ischemic injury, and heart failure. In the initial funding period of this award, we demonstrated that the severity of inflammation in murine models of atherosclerosis could be assessed with contrast-enhanced ultrasound and contrast agents targeted to endothelial cell adhesion molecules (ECAMs). These studies provided important information on binding characteristics, sensitivity of targeting ligands for disease processes. In this competitive renewal we will evaluate the relative clinical utility of this approach. We will determine whether molecular imaging of ECAMs provides unique diagnostic information that could positively impact patient care by guiding therapeutic decisions. One aim is to determine whether CEU targeted to VCAM-1 or P-selectin can detect the earliest stages of atherosclerosis prior to significant lesion development. This capability may be of critical value for assessing risk at a very early stage when novel potent anti-inflammatory therapies would be most effective. Hence, a second aim is to determine whether interventions aimed at the inflammatory response (immunotherapy against oxidized LDL or exercise) are most effective when given at the earliest sign of disease detected by molecular imaging. Sequential imaging studies will be used to determine whether suppression of ECAM expression predicts therapeutic response to treatment. These studies will be performed in two models of disease. The first is a reproducible murine model of atherosclerosis, the LDL-receptor and ApoBec editing peptide knockout, which will provide high-throughput and histologic confirmation. The second will be a novel non-human primate (rhesus macaque) model of obesity, inflammation and atherosclerosis which more closely resembles human disease. This model will be useful for determining the safety and feasibility for imaging with probes that are easily adaptable for human use. These studies will provide information on pathophysiology and response to therapy that will be critical for determining how molecular imaging can play a role for early diagnosis and optimizing management in patients with atherosclerotic disease. PUBLIC HEALTH RELEVANCE: In this proposal, ultrasound imaging of the molecular mediators of atherosclerosis will be used to determine whether the earliest stages of disease can be detected with non-invasive techniques. The overall aim is to determine whether molecular imaging at a very early stage can be used to select for new treatments that may work when given early in the disease process. These studies should provide the basis for the application of molecular imaging in atherosclerosis to improve patient care through early detection and optimization of management.